Project 3: Primary Prevention and Uterine Preservation in Premenopausal Women with Obesity and Endometrial Hyperplasia/Cancer

项目3：绝经前妇女肥胖和子宫内膜增生/癌症的一级预防和子宫保留

• 批准号: 10711638
• 负责人: Andrea Hagemann
• 金额: $ 59.7万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-23 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10711638
• 关键词: Address; Aftercare; Agonist; Atypia; Atypical Endometrial Hyperplasias; Behavior Therapy; Behavioral; Biopsy; Body Weight decreased; Combined Modality Therapy; Development; Diagnosis; Early Diagnosis; Endometrial; Endometrial Carcinoma; Endometrial Hyperplasia; Enrollment; Ensure; Equity; Estrogen Receptors; Estrogens; FDA approved; Fertility; Funding; Future; GLP-I receptor; Genetic Transcription; Hyperplasia; Hysterectomy; Impairment; Injections; Institution; Insulin Resistance; Intrauterine Devices; Levonorgestrel; Live Birth; Malignant Neoplasms; Measures; Metabolism; Obesity; Overweight; Pathology; Patients; Persons; Pharmaceutical Preparations; Placebos; Plasma; Population Sciences; Pregnancy Rate; Premenopause; Prevention; Primary Prevention; Progesterone; Progesterone Receptors; Progestin Therapy; Progestins; Proliferation Marker; Psychologist; Randomized; Randomized, Controlled Trials; Relapse; Route; Serum; Standardization; Telemedicine; Testing; Therapeutic; Time; Tissues; Universities; Uterus; Washington; Weight; Weight Gain; Woman; Work; bariatric surgery; biomarker identification; cancer prevention; efficacy evaluation; experience; improved outcome; insulin secretion; metabolomics; predicting response; premalignant; preservation; prevent; randomized, clinical trials; recruit; response; secondary endpoint; treatment as usual; weight loss intervention

PROJECT SUMMARY/ ABSTRACT Up to 90% of the ~65,000 women diagnosed with endometrial cancer each year in the U.S. are overweight or obese, and up to 60% of endometrial cancer cases are attributed to obesity. This is, in large part, because obesity promotes development of atypical endometrial hyperplasia (AEH), a precursor of grade 1 endometrial cancer. If diagnosed at one of these stages, a patient can be treated with hysterectomy, which is 100% effective in preventing/curing endometrial cancer. However, hysterectomy is often unacceptable to premenopausal women who would like to retain fertility. Instead, such patients are commonly treated with progestin, most commonly via a levonorgestrel-releasing intrauterine device (IUD). However, up to 41% of women on progestin eventually experience relapse and require a hysterectomy. Moreover, fewer than 12% of women who choose this option go on to have a live birth, likely because obesity and the commonly co- occurring insulin resistance impair fertility. As weight loss alone can also reverse AEH and grade 1 endometrial cancer, an ideal treatment for premenopausal women desiring future fertility would be to simultaneously provide a progestin IUD along with an effective weight loss strategy. This Early detection, Prevention and Population Science project includes two randomized controlled trials testing the overall hypothesis that combined treatment with progestin and either therapeutic or behavioral weight loss interventions leads to greater uterine preservation than progestin use alone. Aim 1 is to determine the efficacy of progestin plus a behavioral weight loss intervention to allow uterine preservation and cancer prevention in premenopausal women with AEH or grade 1 endometrial cancer. Aim 2 is to determine the efficacy of a glucagon-like peptide 1 receptor agonist plus progestin plus a behavioral weight loss intervention to allow uterine preservation and cancer prevention in premenopausal women with AEH. The therapeutic drug in this trial is approved by the FDA for treating obesity. Exploratory Aim 3 is to identify biomarkers that reflect response to progestin plus weight loss. If this project identifies effective strategies, they can be widely implemented to allow premenopausal women with AEH or grade 1 endometrial cancer to both avoid cancer and preserve their uterus for future fertility.

项目概要/摘要 在美国，每年约 65,000 名被诊断患有子宫内膜癌的女性中，高达 90% 的人体重过重或体重过重 肥胖，高达60%的子宫内膜癌病例归因于肥胖。这在很大程度上是因为 肥胖促进非典型子宫内膜增生 (AEH) 的发展，这是 1 级子宫内膜的前兆 癌症。如果在这些阶段之一被诊断出来，患者可以接受子宫切除术，这是 100% 有效预防/治疗子宫内膜癌。然而，子宫切除术往往是无法接受的。 希望保留生育能力的绝经前妇女。相反，此类患者通常接受以下治疗： 孕激素，最常见的是通过左炔诺孕酮宫内节育器 (IUD)。然而，高达 41% 服用孕激素的女性最终会出现复发并需要进行子宫切除术。而且，只有不到12%的人 选择此选项的女性会继续活产，可能是因为肥胖和常见的共同因素 发生胰岛素抵抗会损害生育能力。因为单独减肥也可以逆转 AEH 和 1 级子宫内膜异位症 对于希望未来生育的绝经前妇女来说，一种理想的治疗方法是同时治疗癌症 提供孕激素宫内节育器以及有效的减肥策略。这种早期发现、预防和 人口科学项目包括两项随机对照试验，测试总体假设： 孕激素联合治疗和治疗或行为减肥干预措施会导致 比单独使用孕激素更能保护子宫。目的 1 是确定孕激素加 A 的功效 行为减肥干预可在绝经前保留子宫并预防癌症 患有 AEH 或 1 级子宫内膜癌的女性。目标 2 是确定胰高血糖素样肽 1 的功效 受体激动剂加孕激素加上行为减肥干预，以保留子宫和 患有 AEH 的绝经前妇女的癌症预防。本次试验的治疗药物已获得国家药监局批准 FDA用于治疗肥胖症。探索性目标 3 是确定反映孕激素加反应的生物标志物 减肥。如果该项目确定了有效的策略，则可以广泛实施它们，以允许 患有 AEH 或 1 级子宫内膜癌的绝经前女性既要避免癌症又要保护子宫 为了未来的生育能力。